As per ICH guideline Q2(R1), the accuracy is defined as below
“The accuracy of an analytical procedure expresses the closeness of agreement between the value which is accepted either as a conventional true value or an accepted reference value and the value found. This is sometimes termed trueness.”
Accuracy should be assessed over a minimum of 3 concentration levels covering the specified range; by making triplicate preparations at each level.
Accuracy is one of the most critical parameter in method validation. Accuracy confirms the suitability of method to the greatest extent and hence method developer must design suitable extraction procedure to assure accurate quantification of analyte in presence of sample matrix. The diluent and extraction techniques such as shaking/sonication/heating determines the method’s accuracy. The drug product containing drug retarding polymers, such as HPMC, pose great challenge to recovery and such formulations must be handled with utmost precautions.
In today’s article I will walk you through how the accuracy for assay, dissolution and related substances can be performed.
A. Accuracy for Assay:
a. Accuracy for assay of drug substance: As per Q2(R1), the accuracy for assay of a drug substance can be studied from 80 to 120 percent of the test concentration. The accuracy solution at 80%, 100% and 120% can be prepared in triplicate, analysed as per test procedure and %recovery shall be calculated.
Let us understand %recovery calculation with the help of an example of assay of Telmisartan by HPLC.
Let us assume below:
Ø Standard preparation is done by diluting 25.27mg of Telmisartan to 100ml.
Ø The accuracy at 100% is done by adding 25.05mg of Telmisartan Working Std. to 100ml.
Ø The potency of Telmisartan working standard used is 99.8%.
Ø The avg. standard peak area is 500500 and peak area of 100% accuracy solution is 490490
b. Accuracy for assay of drug product: As per Q2(R1), the recovery study for the assay of drug product shall be conducted from 80% to 120% of the test concentration. The accuracy solution at 80%, 100% and 120% can be prepared, analysed as per test procedure and %recovery shall be calculated.
Accuracy can be performed by using drug product by varying the sample quantities with respect to accuracy levels. In case if suitable drug product is not available, accuracy can be performed by spiking suitable amount of API into placebo. Keep the quantity of placebo constant and vary the quantity of API as per accuracy level.
Note: If accuracy study is performed on drug product, consider % assay value (Preferably mean value of precision data) of the drug product for assigning “amount added”.
Evaluation parameters and acceptance criteria:
%Recovery: Between 98.0 to 102.0%
B. Accuracy for dissolution: As per Q2(R1), accuracy for dissolution test can be studied between +/-20 % over the specified range.
a. Accuracy for IR drug product: For example, if the specification for IR product is NLT 80%, the accuracy can be studied from 60% to 100% of the label claim. However, it will be good idea to study accuracy up to 130% to cover the entire range of possible drug release. The accuracy solution at 60%, 80%, 100% and additionally at 130% can be prepared in triplicate, analysed as per test procedure and assessed for %recovery. The accuracy at 130% is recommended by considering the possibility of a content up to 130% in a single unit. Moreover, the highest accuracy level recommended for content uniformity method validation is also 130%.
Accuracy can be performed by using drug product by varying the sample quantities with respect to accuracy levels. In case if suitable drug product is not available, accuracy can be performed by spiking suitable amount of API into placebo. Keep the quantity of placebo constant and vary the quantity of API as per accuracy level.
Note: If accuracy study is performed on drug product, consider % assay value (Preferably mean value of precision data) of the drug product for assigning “amount added”.
Evaluation parameters and acceptance criteria:
%Recovery: Between 95.0 to 105.0%
b. Accuracy for controlled release drug product: If the specification for a controlled released product cover a region from 20%, after 1 hour, up to 90%, after 24 hours, the accuracy can be studied from 0 to 110% of the label claim. However, practically 0% can’t be considered to conduct accuracy, and hence, an LOQ of the method shall be considered. Therefore, in this case accuracy can be studied from LOQ to 110% and additionally at 130% to cover entire range of possible drug release. Refer accuracy for IR drug product for sample preparation, accuracy levels, evaluation parameters & acceptance criteria.
c. Accuracy for delayed release drug product: Dissolution of delayed release drug product is done in two stages viz. acid stage for 2 hours followed by buffer stage for specified time interval such as 30 minutes or 45 minutes. The back assay is calculated for acid stage and % drug release is estimated for buffer stage. The accuracy for ‘back assay method’ as well as ‘drug release at buffer stage’ shall be conducted. Never expose drug product to acid stage during conducting accuracy for ‘back assay method’ or ‘drug release at buffer stage’. The accuracy samples for back assay shall be prepared by taking drug product or by spiking suitable amount of API into placebo and treating the resultant solution as per back assay sample preparation procedure. The accuracy level for back assay can be 80%, 100% and 130%. Triplicate preparation shall be done at each level.
The accuracy samples for buffer stage can be prepared by using drug product or by spiking suitable amount of API into placebo. Accuracy for buffer stage can be studied by making triplicate preparations at each of the three concentration levels between +/-20 % over the specified range. In addition to above, 130% accuracy level can also be considered during buffer stage.
C. Accuracy for related substances: As per Q2(R1), accuracy for impurities can be studied from the reporting level of an impurity to 120% of the specification with three different levels and triplicate preparations at each level. The reporting level can be an LOQ. The accuracy solutions with concentration of LOQ, 100% and 120% can be prepared in triplicate at each level.
The concentration of impurities across accuracy levels is depends on release and shelf life specification of impurities. The accuracy levels shall be designed in such a way that both release and shelf life specification of impurity must get covered. To further explain it, let us take an example of Telmisartan tablets having Impurity A and Impurity B with specification as described in below table.
The specification of impurity in terms of ‘%’ must be first converted to ‘ppm’ and to do that, one must know the concentration of Telmisartan in test preparation.
Let us assume that the concentration of Telmisartan in test preparation is 500 ppm. To convert limit from ‘%’ to ‘ppm’, analyst need to consider concentration of Telmisartan in test preparation as 100%
Therefore, 100% = 500ppm
Hence 0.2% of Impurity A = 1 ppm
Refer below table for limit of impurity in ‘%’ and ‘ppm’.
Having understood the concentration of Impurity-A at release and shelf life specification, one must select higher accuracy levels for impurity A in such a way that 120% of highest specification (3 ppm is the highest specification and 120% of 3ppm will become 3.6ppm) must get covered. Similarly, accuracy levels for Impurity B also can be calculated.
Refer below table for the possible accuracy levels of Impurity A and Impurity B.
Note: The concentration in % is mapped against release specification concentration. The accuracy levels more than 3 are considered due to wide concentration range.
Based on above table, one can understand that the highest concentration requirement is met for both Impurity A and Impurity B.
In case of drug substance, accuracy of related substances can be carried out by spiking known impurity into API.
The accuracy of related substances for drug product can be performed by spiking suitable amount of impurities into drug product. Alternatively, in case if drug product is not available- accuracy can be carried out by using a blend prepared by mixing placebo with API at suitable proportions. Accuracy for unknown impurity shall be performed with the help of API. The API can be spiked in to equivalent amount of placebo present in test preparation at suitable levels ranging from LOQ to 120% of highest unknown impurity specification.
I have tried to explain how the accuracy for assay, dissolution and related substances can be conducted for drug substance and drug product. The study design and approach may change lab to lab and that is not only Ok but quite expected. Please revert or comment on which approach you follow for accuracy study? What are your 3 takeaways from this article? Please do respond!
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